The pathophysiology of pediatric chronic rhinosinusitis (CRS) is not well understood, but bacterial and viral pathogens and environmental agents are thought to play a critical role in initiating the immune responses that result in inflammation, mucus hypersecretion and obstruction that characterize this disease. Histological and immunohistochemical studies of pediatric CRS are restricted to analyses of the sinus mucosa at end stages of pathology and after having been exposed to multiple courses of steroids and antibiotics. Moreover, the availability of sinus mucosal samples is limited due to difficulties collecting surgical specimens that are sufficiently well preserved for study. Submucosal gland hyperplasia/hypertrophy is the key histopathological change identified in the tissues of these patients and likely the source of the mucous hypersecretion seen in pediatric CRS. In order to address the limitations delineated above in the context of the known histological changes described in pediatric CRS, we have proposed to develop 3- dimensional in vitro models of glandular hyperplasia that mimic the in vivo histological features seen in the sinus tissues of these patients in the two major phenotypes expressed in pediatric CRS, e.g. with and without nasal polyps. The fidelity of these models to in vivo sinus mucosa will be validated by immunohistochemistry using the sinus tissues of children with CRS and functionally by determining the bacterial pathogen byproducts and/or immune response mediators implicated in CRS that promote glandular hyperplasia. These models will revolutionize the understanding of CRS by permitting investigators to study the histological and molecular changes of the pediatric sinus mucosa in real time and sequentially follow the evolution of the disease in relevant clinical presentations. The use of these models will have tremendous advantages in the development of pharmacologic interventions that will safely and effectively treat, and ultimately cure, pediatric CRS. PUBLIC HEALTH RELEVANCE: Chronic rhinosinusitis (CRS), a highly prevalent chronic disease, is characterized by chronic inflammation of the sinus mucosa and mucus hypersecretion caused by the increased number of glands in the sinus mucosa. This project will develop 3-dimenstional models using control and CRS sinus epithelial cells to investigate how inflammation triggers the histological and molecular changes that occur in the sinus mucosa of CRS patients, which models will be useful to evaluate pharmacologic agents that can treat CRS patients safely and effectively.!